Phosphorylation of Mineralocorticoid Receptor Ligand Binding Domain Impairs Receptor Activation and Has a Dominant Negative Effect over Non-phosphorylated Receptors

• Published in: The Journal of biological chemistry Vol. 291; no. 36; pp. 19068 - 19078
• Main Authors: Jiménez-Canino, Rubén, Fernandes, Miguel X., de la Rosa, Diego Alvarez
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.09.2016; American Society for Biochemistry and Molecular Biology
• Subjects: Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - genetics; aldosterone; Amino Acid Substitution; Animals; Cell Biology; Cell Nucleus - genetics; Cell Nucleus - metabolism; Chlorocebus aethiops; cortisol; COS Cells; gene transcription; glucocorticoid receptor; Humans; kidney; Mice; mineralocorticoid receptor; Mutation, Missense; Phosphorylation; Protein Binding; Receptors, Mineralocorticoid - agonists; Receptors, Mineralocorticoid - chemistry; Receptors, Mineralocorticoid - genetics; Receptors, Mineralocorticoid - metabolism; steroid hormone receptor; Transcriptional Activation - drug effects; Transcriptional Activation - physiology; kidney; cortisol; gene transcription; glucocorticoid receptor; aldosterone; mineralocorticoid receptor; steroid hormone receptor; phosphorylation
• DOI: 10.1074/jbc.M116.718395
• ISSN: 0021-9258

Post-translational modification of steroid receptors allows fine-tuning different properties of this family of proteins, including stability, activation, or interaction with co-regulators. Recently, a novel effect of phosphorylation on steroid receptor biology was described. Phosphorylation of human mineralocorticoid receptor (MR) on Ser-843, a residue placed on the ligand binding domain, lowers affinity for agonists, producing inhibition of gene transactivation. We now show that MR inhibition by phosphorylation occurs even at high agonist concentration, suggesting that phosphorylation may also impair coupling between ligand binding and receptor activation. Our results demonstrate that agonists are able to induce partial nuclear translocation of MR but fail to produce transactivation due at least in part to impaired co-activator recruitment. The inhibitory effect of phosphorylation on MR acts in a dominant-negative manner, effectively amplifying its functional effect on gene transactivation.